In this study, we defined the role of peroxisome proliferator-activated receptor ␤͞␦ (PPAR␦) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPAR␦ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPAR␦ controls fatty acid oxidation by regulating genes involved in fatty acid transport, ␤-oxidation, and mitochondrial respiration. Similar PPAR␦-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid ␤-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid ␤-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob͞ob mice. These data suggest that PPAR␦ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.obesity ͉ insulin resistance ͉ thermogenesis ͉ pancreatic ␤-cell ͉ PGC-1␣

Hepatocyte nuclear factor-4alpha (HNF4alpha) exists in multiple isoforms that are generated by alternative promoter (P1 and P2) usage and splicing. Here we establish monoclonal antibodies (mAbs) for detecting P1 and P2 promoter-driven HNF4alpha, and evaluate their expression in normal adult human tissues and surgically resected carcinomas of different origins. Using immunohistochemical analysis, we demonstrate that, while P1 promoter-driven HNF4alpha is expressed in hepatocytes, small intestine, colon, kidney and epididymis, P2 promoter-driven HNF4alpha is expressed in bile duct, pancreas, stomach, small intestine, colon and epididymis. Altered expression patterns of P1 and P2 promoter-driven HNF4alpha were observed in gastric, hepatocellular and colorectal carcinomas. HNF4alpha was expressed in lung metastases from renal cell, hepatocellular and colorectal carcinoma but was not observed in lung tumours. The P1 and P2 promoter-driven HNF4alpha expression pattern of tumour metastases correlated with the primary site of origin. P1 promoter-driven HNF4alpha was also found in intestinal metaplasia of the stomach. These data provide evidence for the tissue distribution of P1 and P2 promoter-driven HNF4alpha at the protein level and suggest that HNF4alpha may be a novel diagnostic marker for metastases of unknown primary. We propose that the dysregulation of alternative promoter usage of HNF4alpha is associated with the pathogenesis of certain cancers.

/npsi/ctrl?lang=en http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/ctrl?lang=fr Access and use of this website and the material on it are subject to the Terms and Conditions set forth at http://nparc.cisti-icist.nrc-cnrc.gc.ca/npsi/jsp/nparc_cp.jsp?lang=en NRC Publications Archive Archives des publications du CNRCThis publication could be one of several versions: author's original, accepted manuscript or the publisher's version. / La version de cette publication peut être l'une des suivantes : la version prépublication de l'auteur, la version acceptée du manuscrit ou la version de l'éditeur. Science, 7, Part A-1, pp. 3151-3158, 1970-02-01 Thermal decomposition products of poly(vinyl alcohol) Tsuchiya, Y.; Sumi, K. Journal of Polymer SynopsisThe thermal decomposition of poly(viny1 alcohol) is known to occur in two stages. In a study of firststage decomposition, this polymer was pyrolyzed in vacuum at 240°C for 4 hr and the products were determined by using gas chromatography. The main products were water, aldehydes having the general formula HC+CH=CII-fCI-13, and I I n 0 methyl ketones having the formula RJC-C+CH=CH-fCI-13, where n = 0, 1, 2, 3, etc.

Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4␣ (HNF4␣) in the ABCG5/ABCG8 intergenic promoter, through which HNF4␣ strongly activated the expression of a reporter gene in both directions. The HNF4␣-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4␣. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4␣ leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4␣ and GATA were essential for maximal synergism. We also show that HNF4␣, GATA4, and GATA6 colocalize in the nuclei of HepG2 cells and that a physical interaction between HNF4␣ and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4␣ acts synergistically with GATA factors to activate gene expression in a bidirectional fashion.Cholesterol homeostasis is maintained by a series of regulatory pathways that control the synthesis of endogenous cholesterol, the absorption of dietary sterol, and the elimination of cholesterol and its catabolic end products, bile acids. Transcriptional control of many genes vital to these processes can be attributed to two classes of transcription factors: sterol regulatory element-binding proteins (SREBPs), especially SREBP-2, which control the production of key enzymes in cholesterol biosynthesis (11,36,38,39), and the nuclear hormone receptor family, including liver X receptor (LXR), farnesoid X receptor, small heterodimer partner, liver receptor homolog1 (LRH-1), and hepatocyte nuclear factor 4␣ (HNF4␣), which control the expression of genes involved in cholesterol efflux, catabolism, and elimination (3, 27).HNF4␣ is the most abundant nuclear orphan receptor expressed in the liver, and it is involved in early liver development (22). HNF4␣ is also expressed in kidney, intestine, and pancreas and is required for expression of many tissue-specific traits in all of these organs. Transcriptional activation by HNF4␣ is mediated by its binding as a homodimer to a DNA sequence composed of two direct repeats (DRs) of the hexanucleotide motif AGGTCA separated by 1 base, referred to as an HNF4␣ response element of the DR-1 type. Like other nuclear receptors, HNF4␣ exhibits a modular structure with six distinct domains (A to F). The N-terminal A/B domain is highly variable among nuclear receptors and contains a ligandindependent activation function 1 (AF-1) domain. The highly conserved C domain encodes the DNA binding domain of nuclear receptors and confers sequence-specific DNA recognition. By linking the highly structured C and E domains, the hinge D region may allow for flexibil...